Protein reveals HIV vaccine targets

UC DAVIS (US) — A component of a potential vaccine opens to rearrange proteins and to possibly reveal new targets to prevent HIV infection and AIDS.

The research is published online in the journal Proceedings of the National Academy of Sciences.

An international team of researchers from the U.S., Sweden, and France studied the structure and behavior of the HIV envelope protein complex, which could serve as a component of a vaccine that encourages the human immune system to generate antibodies against HIV.

“By opening up these less exposed regions, we might be able to raise more broadly cross-reactive antibodies to HIV,” says R. Holland Cheng, professor of molecular and cellular biology at University of California, Davis and senior author of the study.

HIV infects a type of white blood cell called the CD4 T cell, weakening the immune system and leading to AIDS.

HIV attaches to these cells through the envelope protein complex, which is made up of three gp120 proteins and three gp41 proteins.

First, the gp120 protein attaches to a CD4 protein on the victim cell’s membrane, then uses gp41 to punch a hole through it.

Researchers used a cryoelectron microscope to study the structure of the complex and how it changes when exposed to a piece of the CD4 protein.

A cryoelectron microscope derives three-dimensional images of complex protein structures from samples frozen in liquid nitrogen.

When the HIV protein complex attaches to a CD4 protein, it rotates and flattens, exposing more of the gp41 proteins in the middle—probably allowing the gp41 protein to get closer to the cell membrane so it can lock on.

It also potentially exposes an area of the virus that would be vulnerable to attack by the immune system, Cheng says.

But if a person were vaccinated and had antibodies to such a protein region, they might be able to stop the virus at the point of invading the CD4 T cell.

The gp120 protein itself varies considerably between strains, so it has been difficult to make an effective vaccine against it.

But these hidden protein regions vary less between different strains of HIV, Cheng says.

Cheng’s group is part of the HIV Research and Design consortium formed by the National Institutes of Health to pursue new targets for HIV vaccines.

In future work, the consortium plans to test potent antibodies from HIV-positive people who have survived without developing AIDS to see if the antibodies recognize the new potential vaccine targets.

The National Institutes of Health funded the work.

At top, the orange shape shows the three-armed HIV envelope protein, seen from above, before attaching to the CD4 protein. The green shape shows how it opens and twists after attaching to CD4 (dark blue ribbon on the green shape). At bottom, a side view of the HIV protein before (orange) and after (green).

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